This invention relates to immunostimulatory nucleic acids, to compositions which contain them, and to the use of the immunostimulatory nucleic acids to treat various conditions and disorders, including cancer.
Several classes of immunostimulatory nucleic acids are known. Although many share an unmethylated cytosine-guanine (CpG) base sequence motif, they also possess structural differences that produce distinct immunostimulatory activities that characterize each class. See, e.g., Krieg, A M (2006) Nature Reviews Drug Discovery 5:471-84; Jurk, M et al. (2004) Immunobiology 209:141-54; Vollmer, J et al. (2004) Eur. J. Immunol. 34:251-62; Krieg, A M (2001) Trends in Microbiology 9:249-52. For example, A-class CpG oligodeoxyribonucleotides (ODN) typically include nuclease-resistant (stabilized) base sequences comprised of three or more consecutive guanines (poly-G motifs) at one or both ends, and a central region comprised of one or more CpG dinucleotides contained in a self-complementary palindrome. Members of A-class CpG ODN activate natural killer (NK) cells and induce interferon-alpha (INF-α) secretion from plasmacytoid dendritic cells (pDC). B-class CpG oligodeoxyribonucleotides typically include a stabilized non-palindromic nucleotide sequence, which comprises one or more CpG dinucleotides. In contrast to A-class ODN, B-class CpG oligodeoxyribonucleotides strongly activate B cells, but induce comparatively weaker INF-α secretion.
Commonly assigned, published international patent application WO 03/015711 (the '711 application) describes a third class of immunostimulatory nucleic acids. C-class CpG oligodeoxyribonucleotides typically include one or more CpG motifs, which are located within the 5′-region, and a palindromic sequence, which is located at or near the 3′-end. They exhibit immunostimulatory activity that is characteristic of both A-class and B-class CpG ODN, including induction of INF-α secretion and activation of NK cells. At similar concentrations, C-class oligodeoxyribonucleotides generally exhibit B cell activation that is greater than what is observed with A-class CpG ODN, but is less than what is typically seen with B-class CpG ODN.
Recent studies have shown that CpG oligodeoxyribonucleotides induce immunostimulatory activity through interaction with Toll-like receptor 9 (TLR9). See Rutz, M et al. (2004) Eur. J. Immunol. 34:2541-50; Bauer, S et al. (2001) Proc. Nat'l Acad. Sci. USA 98(16):9237-42; and Latz, E et al. (2004) Nature Immunol. 5(2):190-98. A number of TLR9 agonists have been evaluated, or are currently undergoing evaluation, in human clinical trials related to infectious diseases, cancer, and allergy-related disorders. See, e.g., Krieg, A M (2006) Nature Reviews Drug Discovery 5:471-84.